Summary of Work: Retinoids are important regulators of development, cell growth and differentia- tion. Many of the effects of retinoids on gene expression are mediated through the nuclear retinoid receptors RARs and RXRs. However, the actions of certain retinoids such as retinoid 6-[3-(1- adamantyl)-4-hydroxy- phenyl]-2-naphthalene- carboxylic acid (AHPN) are not mediated by these nuclear receptors. AHPN inhibits the proliferation and induces apoptosis in many lung carcinoma cell lines. BrdU incorporation and flow cytometric analyses indicated that treatment of H460 cells with AHPN induces G1 cell cycle arrest. We, therefore, investi- gated the effect of AHPN on several G1 cell cycle regulatory proteins. The cell cycle arrest induced by AHPN is accompanied by an inhibition in the hyperphos- phorylation of the Rb protein, an indication of G1 arrest. Further, two cyclin- dependent kinases, cdk2 and cdk4, normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partially related to an increase in p21WAF1/Cip1 (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin- dependent kinase inhibitor p27Kip1. The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a posttranscriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines different mechanisms appear to be involved. The specificity by which AHPN and other retinoids induce growth arrest and apoptosis indicates that AHPN action is not mediated by RAR or RXR receptors but involves a novel signaling pathway.